Risk of pneumonia among patients with chronic kidney disease in
outpatient and inpatient: a nationwide population-based study
Che-Yi Chou1,2, Shu-Ming Wang1,2, Chih-Chia Liang1,2, Chiz-Tzung Chang1,2, Jiung-Hsiun Liu1,2, I-Kuan Wang1,2, Lien-Cheng Hsiao2,3, Chih-Hsin Muo4,5, Chiu-Ching Huang1,2, Chi-Jung Chung6,7
1 Division of Nephrology and Kidney Institute, Department of Internal Medicine,
China Medical University Hospital, Taichung 40447, Taiwan
2College of Medicine, China Medical University, Taichung 40402, Taiwan
3Division of Cardiology, Department of Internal Medicine, China Medical University
Hospital, Taichung, Taiwan
4Department of Public Health, China Medical University and Hospital, 91 Hsueh-Shih
Road, Taichung 404, Taiwan
5Management Office for Health Data, China Medical University and Hospital, 91
Hsueh-Shih Road, Taichung 404, Taiwan
6Department of Health Risk Management, College of Public Health, China Medical
University, Taichung, Taiwan
7Department of Medical Research, China Medical University Hospital, Taichung,
Taiwan
Department of Health Risk Management, College of Public Health, China Medical University, No. 91 Hsueh Shih Road, Taichung City 404, Taiwan
E-mail: [email protected] Tel: 886-4-22053366-6505 Fax: 886-4-2207-0429
Abstract
Chronic kidney disease (CKD) patients are more at risk for pneumonia than the general population. Patients with pneumonia were usually treated in outpatients, but previous studies were conducted based on inpatient pneumonia. This may under-estimate the risk of pneumonia in patients with CKD. We investigated the pneumonia risk in both outpatient and inpatient settings in CKD patients.
Method
A total of 15562 CKD patients and 62109 non-CKD individuals (matched for age and gender) in the Longitudinal Health Insurance Database of Taiwan National Insurance from 1996 to 2010 were analyzed. Incidence density rates of inpatient and outpatient pneumonia were calculated. Risk factors associated with pneumonia were analyzed using Cox proportional hazards models with adjustments for confounders.
Results
The incidence density rate of pneumonia was 65.6 per 1000 person-years in CKD patients and 28.4 per 1000 person-year in non-CKD individuals. The incidence density rate of inpatient pneumonia was 43.3 per 1000 person-years in CKD patients and 16.6 in non-CKD individuals. CKD was associated with increased risk for pneumonia [adjusted hazard ratio (aHR): 1.97, 95% CI (confidence interval): 1.89-2.05, p<0.001], outpatient pneumonia (aHR: 1.40, 95 % CI: 1.31-1.49), and inpatient pneumonia (aHR: 2.17, 95% CI: 2.07-2.29, p<0.001). Patients’ comorbidity including
diabetes, cardiovascular disease, asthma, and chronic obstructive pulmonary disease were independently associated with increased risk of pneumonia.
Conclusion
Chronic kidney disease is associated with increased risk of both outpatient and inpatient pneumonia. This association is independent of comorbid diabetes, cardiovascular disease, asthma and chronic obstructive pulmonary disease.
Introduction
Pneumonia is one of the most common infectious morbidity in chronic kidney disease (CKD) patients. Pneumonia in CKD patients is associated with increased hospitalization, cardiovascular event and mortality . Pneumonia related mortality rate of CKD patients is 14 to 16 fold higher than that of general population 4. The risk of inpatient pneumonia and mortality within 30 days is increased with the decline of renal function in CKD patients 5. However, all the previous studies were based on the incidence of inpatient pneumonia. This may underestimate the risk of pneumonia because most treatment for pneumonia was provided in outpatient settings. The aim of the study is to determine the incidence of both inpatient and outpatient pneumonia in CKD patients using the National Health Insurance (NHI) data from Taiwan.
Material and Methods
This is as a retrospective cohort study using an encrypted database from the Bureau of National Health Insurance (BNHI). The Institutional Review Board of China Medical waved the need for informed consent. The Longitudinal Health Insurance Database (LHID) of the Taiwan National Health Research Institute (NHRI) was released by the BNHI. The LHID included all medical records from 1996 to 2010, from which one million people were randomly selected. There were no significant differences in the sex and age distributions between LHID and all individuals in the NHRI. The
International Classification of Disease Revision 9th Clinical Modification (ICD-9-CM) was used for the diagnosis codes. A 1:4 study design was used as the increase of controls did not increase statistical efficiency 6.
Study sample
CKD patients was defined as patients with a ICD-9-CM codes 585 from LHID who is not in catastrophic illness patients database that include patients with CKD stage 3 to 5 without renal replacement therapy (Figure 1) 7. A total of 15562 CKD patients and 62109 non-CKD patients (matched for age and sex) were included. Pneumonia was identified using ICD-9-CM codes 481, 482, 485 and 486 and pneumonia related hospitalization was also recorded. For patients who developed more than one episode of pneumonia, the first episode of pneumonia was recorded. As we focused on primary pneumonia risk, patients with pneumonia before the diagnosis of CKD were excluded. Time was calculated from the index date of CKD to the date of pneumonia. Co-morbidities including diabetes (ICD-9-CM codes 250), hypertension (401-405), cardiovascular disease (CVD) (410-414), asthma (493) and chronic obstructive pulmonary disease (COPD) (491, 492, 494, 496) are defined as more than three medical visits.
Statistical analysis
Distribution of sex, age, and co-morbidities for CKD patients and control individuals were analyzed using chi-square test for categorical variables or t-test for continuous
variables. The incidence density was defined as the number of pneumonia cases divided by the total follow-up person-years (expressed as per 1000 person-years). The adjusted hazard ratio (aHR) and the 95 % confidence intervals (CIs) of pneumonia risk factors were analyzed using Cox proportional-hazards regression with adjustment for sex, age, hypertension, diabetes, cardiovascular disease (CVD), asthma, and COPD. The statistical significance level was set at a two-tailed probability value of < 0.05. All analyses was performed using the SAS software version 9.1 (SAS Institute, Cary, NC, USA).
Results
The incidence density rate of pneumonia was 65.6 in CKD patients and 28.4 per 1000 person-years in non-CKD patients (Table 1). The incidence density rate was used because the follow-up of non-CKD patients was longer. The incidence density rate of inpatient pneumonia was 43.3 per 1000 person-years in CKD patients and 16.6 per 1000 person-years in non-CKD patients. CKD patients had a higher rate of diabetes (p<0.001), hypertension (p<0.001), CVD (p<0.001), asthma (p<0.001) and COPD (p<0.001) than non-CKD patients did. Compared to patients without pneumonia, patients who developed pneumonia were older and they were more likely to have CKD, diabetes, hypertension, and CVD, asthma and COPD (Table 2). Of 5536 patients with outpatient pneumonia, 1375 (24.8%) of them had CKD. Of 7240
patients with inpatient pneumonia, 2661 (36.8%) of them had CKD. The patients with inpatients pneumonia were older than the patients with outpatient pneumonia. Compared to patients with outpatient pneumonia, patients with inpatients pneumonia were more likely to have diabetes, hypertension and CVD. The percentage of patients with asthma was lower in inpatients patients compared to the patients with outpatient pneumonia. The prevalence of patients with COPD was not different between the patients with inpatient pneumonia and those with outpatient pneumonia.
CKD, patients’ age, male gender, hypertension, diabetes, CVD, asthma, and COPD were associated with increased risk of pneumonia (Table 3). The aHR of CKD for any type of pneumonia was 1.97 (95% CI: 1.89-2.05, p < 0.001), 1.40 (95% CI: 1.31-1.49) for outpatient pneumonia, and 2.17 (95% CI: 2.07-2.29) for inpatient pneumonia. Male gender (aHR 1.13, 95% CI: 1.07-1.19), comorbid diabetes (aHR 1.12, 95 % CI: 1.05-1.19), comorbid CVA (aHR 1.11, 95% CI: 1.04-1.20), comorbid asthma (aHR 1.66, 95% CI: 1.56-1.79), and comorbid COPD (aHR 1.89, 95% CI: 1.77-2.02) was independently associated with increased outpatients pneumonia risk. The comorbid hypertension was not associated with increased outpatients pneumonia risk, but was associated with increased inpatient pneumonia risk (aHR 1.10, 95 % CI: 1.04-1.16).
Discussions
pneumonia. Compared to non-CKD patients, the risk of all pneumonia in CKD patients was 1.97-fold higher, 1.4 fold higher for outpatient pneumonia, and 2.17 fold higher for inpatient pneumonia. CKD patients not only had increased risk of pneumonia but also increased severity of pneumonia (indicated by hospitalization) than non-CKD patients. The incidence of pneumonia in this study was higher than the incidence of pneumonia reported in the previous studies because outpatient pneumonia was taken into consideration in this study. The increased infection risk in CKD patients can be explained by uremia related impairment in monocyte 12, neutrophil phagocytosis 13, T-lymphocytes 14, B-lymphocytes 15 and increased cytokines 16. The increased risk of inpatient pneumonia in CKD patients may be related to the comorbidity of patients with CKD because comorbidities were associated with severity of pneumonia .
The percentage of inpatient pneumonia was 58.6% in non-CKD patients who developed pneumonia and 65.9% in CKD patients who developed pneumonia. The high hospitalization rate of pneumonia can be explained by two reasons. First, the hospitalization costs in Taiwan are low. Second, most of the hospitalization cost was covered by the health insurance and the patients only need to pay 10% of the cost. The high rate of diabetes, hypertension, CVD , asthma and COPD in CKD patients was consistent to the findings of the previous studies .
There were some limitations of this study. First, the ICD-9-CM code 585.1-585.5 for CKD 1-5 was not used and the incidence of CKD can be under-estimated using ICD-9-CM code 585 (patients with CKD 1 and patients with CKD 2 were not included). Second, variables of pneumonia severity index such as mental status, vital signs and laboratory data were not available in the LHID. Third, the pneumonia pathogen that was associated with the severity of pneumonia 23 was not recorded in the LHID. We were not able to determine if any specific pathogen was related to the pneumonia in CKD patients.
In conclusion, chronic kidney disease patients have increased risk for inpatient and outpatient pneumonia, especially pneumonia that required hospitalization. The increased risk of pneumonia in CKD patients is independent of their comorbidity.
Disclosure
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Acknowledgements
We thank the National Health Research Institute in Taiwan for providing the insurance claims data. This study was supported in part by the Executive Yuan National Science Council (grant number NSC 98-2621-M-039 -001), Clinical Trial and Research Center of Excellence of the Department of Health (grant number DOH101-TD-B-111-004), Taiwan Department of Health Cancer Research Center of Excellence (grant number DOH101-TD-C-111-005) and the China Medical University Hospital (grant number 1MS1).
Table 1. Demographic data of patients with and without chronic kidney disease (CKD)
Clinical characteristics Non-CKD
n=62109
CKD n=15562
Pneumonia (per 1000 person-years) 8740 28.4 4036 65.6 <0.001 Inpatients (per 1000 person-years) 5125 16.6 2661 43.3 <0.001 Follow-up (years) 5.0 (0.1-11) 4.0 (0.1-11) <0.001 Male n % 35950 57.9 9011 57.9 0.96 Age, year n(%) < 45 7964 12.8 1991 12.8 >0.99 45-54 8900 14.3 2225 14.3 55-64 11700 18.8 2925 18.8 65-74 16464 26.5 4116 26.5 ≥ 75 17081 27.5 4305 27.7 Mean (SD) 63.3 (16.0) 64.0 (16.0) Comorbidity n % Diabetes 9428 15.2 5653 36.3 <0.001 Hypertension 28256 45.5 11614 74.6 <0.001 CVD 21091 34.0 8771 56.4 <0.001 Asthma 4281 6.9 1676 10.8 <0.001 COPD 9305 15.0 3787 24.3 <0.001
*Pneumonia that required hospitalization, CVD: cardiovascular disease, COPD: chronic obstructive pulmonary disease
Table 2. Characteristics of patients with and without pneumonia Clinical characteristics Pneumonia (-) n=64895 Pneumonia (outpatient) n=5536 Pneumonia (inpatient) n=7240 CKD n % 11526 17.8 1375 24.8a 2661 36.8a,b Male n % 37126 57.2 3299 59.6a 4536 62.7a,b Age n % < 45 9311 14.4 453 8.2a 191 2.6a,b 45-54 10261 15.8 508 9.2a 356 4.9a,b 55-64 12952 20.0 880 15.9a 793 11.0a,b 65-74 16839 26.0 1671 30.2a 2070 28.6a,b ≥ 75 15532 23.9 2024 36.7a 3830 52.9a,b Comorbidity n % Diabetes 11560 17.8 1260 22.8a 2261 31.2a,b Hypertension 31142 48.0 3414 61.7a 5314 73.4a,b CVD 22692 35.0 2800 50.6a 4370 60.4a,b Asthma 4097 6.3 886 16.0a 974 13.5a,b COPD 8900 13.7 1800 32.5a 2392 33.0a
CKD: chronic kidney disease, CVD: cardiovascular disease, COPD: chronic obstructive pulmonary disease
a p < 0.05 in Chi-square test compared to patients without pneumonia
Table 3. Hazard ratio of pneumonia risk factors
Risk factors Pneumonia (overall) Pneumonia (outpatient)
Pneumonia (inpatient)
aHR (95% CI) aHR (95% CI) aHR (95% CI)
CKD 1.97 (1.89-2.05) 1.40 (1.31-1.49) 2.17 (2.07-2.29) Age (every 10 additional years) 1.05 (1.05-1.05) 1.02 (1.02-1.03) 1.07 (1.07-1.07) Male 1.24 (1.20-1.29) 1.13 (1.07-1.19) 1.37 (1.31-1.44) Hypertension 1.09 (1.04-1.15) 1.03 (0.96-1.11) 1.10 (1.04-1.16) Diabetes 1.29 (1.24-1.34) 1.12 (1.05-1.19) 1.22 (1.14-1.30) CVD 1.08 (1.07-1.14) 1.11 (1.04-1.20) 1.10 (1.04-1.16) Asthma 1.39 (1.32-1.46) 1.66 (1.53-1.79) 1.20 (1.12-1.28) COPD 1.60 (1.54-1.67) 1.89 (1.77-2.02) 1.41 (1.34-1.49) CKD: chronic kidney disease, CVD: cardiovascular disease, COPD: chronic obstructive pulmonary disease, aHR: adjusted hazard ratio, adjusted for age, sex, diabetes, hypertension, CVD, asthma and COPD.
Figure 1. Flow chart of study design
NHI: national health insurance, CKD: chronic kidney disease, LHID: longitudinal health insurance database
Taiwan NHI Database Individuals without CKD
diagnosed before the index date
20179 CKD patients from LHID 2000 database in 2000-2010 2000-2009
Follow-up to the end of 2010 Compare risk of pneumonia
Excluded patients with pneumonia before CKD 15562 CKD patients in final analysis 62109 controls in final analysis
4:1 Frequency matched with age, sex and index date. Excluded people with pneumonia before index date
